Dissecting the Contribution of OATP1B1 to Hepatic Uptake of Statins Using the OATP1B1 Selective Inhibitor Estropipate.

Identification of a selective inhibitor of organic anion transporting polypeptide (OATP) 1B1 is critical in order to determine the contribution of OATP1B1-mediated uptake of investigational drugs into human hepatocytes for successful in vitro-to-in vivo extrapolation (IVIVE) of hepatic uptake and drug-drug interaction (DDI). The following study examined the inhibitory effects of estropipate (EPP) on major sinusoidal drug uptake transporters and explored its utility regarding IVIVE of statin hepatic disposition. EPP and its free-base form (i.e., estrone sulfate) showed a potent and high degree of selectivity in inhibiting the OATP1B1-mediated transport of rosuvastatin with an IC value averaging 0.05 ± 0.01 and 0.12 ± 0.07 μM for human and cynomolgus monkey OATP1B1 (hOATP1B1 and cOATP1B1), respectively, whereas weak inhibition was observed for human and monkey OATP1B3, OATP2B1, sodium-taurocholate cotransporting polypeptide (NTCP), organic anion transporter 2, and organic cation transporter 1 with IC values ranging from 8.6 to 64.0 μM. EPP, together with rifamycin SV, was subsequently used to determine the fractions of hepatic uptake clearance ( f) of statins, including rosuvastatin, pitavastatin, and dehydropravastatin, which are reported to be mediated by OATP1B1, OATP1B3, OATP2B1, and NTCP. Finally, the magnitudes of in vivo inhibition of rosuvastatin clearance caused by EPP and rifampin in cynomolgus monkeys were predicted by using individual transporter IC and f (AUC fold change 1.28 vs 1.21, 2.71 vs 1.75, and 3.35 vs 2.83, respectively). These results suggest that EPP is an appropriate OATP1B1-selective inhibitor to establish the relative contribution of OATP1B1 to hepatic uptake in vitro and to discern the role of OATP1B1 in hepatic disposition in vivo.